2
AGE AND GENDER RELATED DIFFERENCES
IN RENAL CELL CARCINOMA IN A EUROPEAN
COHORT
Miki Hew, Rens Zonneveld, Intan Kümmerlin, Dedan Opondo, Jean de la
Rosette, Pilar Laguna
Department of Urology, Academisch Medisch Centrum, Amsterdam
The Journal of Urology July 2012, Volume 188, Issue 1, Pages 33-38
Chapter 2
AGE AND GENDER RELATED DIFFERENCES IN RCC IN A EUROPEAN COHORT
ABSTRACT
INTRODUCTION
Purpose
To evaluate the influence of age on gender related differences in renal
cell carcinoma (RCC) presentation of patients operated between 1995
and 2005 in a European country and to assess the trend in missing
pathological data.
Material and Methods
Data of all patients who underwent radical or partial nephrectomy for
RCC during 1995-2005 in the Netherlands were retrospectively collected
from the prospective PALGA database. Patients were divided into five
cohorts based on age at surgery (≤40; 41-50; 51-60; 61-70; and >70
years). Variables evaluated were gender differences for age, tumour size,
subtype, tumour stage and Fuhrman grade.
Results
A higher mean age in women was only observed in patients older than 70
years (p<0.001). Male to female ratio was 2:1 between 41-60 years and
1.2:1 in patients older than 70. Compared to men, women had smaller
tumour size between 51-60 years (p=0.03), tumour stage pT3 was less
frequent from 41 years onward (p=0.02) and grade 2 was less frequent from
61 years onward (p<0.001). Percentages of tumours with missing stage
(14.9%), subtype (52.2%) and grade (47.1%) diminished substantially
during the study period (p<0.001).
Conclusions
An older age in women presenting at surgery for RCC was only prevalent
in patients over 70 years. The male to female ratio was almost equal
in patients over 70 years, compared to 2:1 between 41 and 60 years.
Women presented with less pT3 tumours than men from the age of 41
years onwards. Missing pathological data diminished significantly between
1995 and 2005.
Broad epidemiological studies from United States databases (NCDB
(National Cancer Database) and SEER (Surveillance Epidemiology and
End Results)) have independently explored gender differences in the
presentation of renal cell carcinoma. Their conclusions indicated that
women were more likely to present with RCC at an older age, with lower
stage and smaller tumours when compared to men 1,2.
These gender discrepancies remain poorly understood. Suggested
hypotheses, including hormonal influence, occupational exposure to
chemicals, differences in symptomatic presentation and imaging patterns,
do not provide sufficient explanation 3-5.
Currently large population-based assessment of RCC differences
between genders is only available for the USA and data extrapolation to
the European population has simply been assumed. European or Asian
studies are limited by their retrospective nature and by inclusion of data
originating mostly in reference centres 6. Furthermore careful interpretation
is warranted due to the fact that the existent databases do not provide
with a complete national coverage and contain large amounts of missing
pathological data, concerning subtype, stage and grade 1,2.
PALGA (Pathological Anatomical National Automated Archive) is a
Dutch nationwide pathology network and archive. The database provides
pathology reports generated in the Netherlands from 1991 onwards.
Central reporting to PALGA became mandatory in 1995 7.
2
Objectives of this study are to evaluate the influence of age on gender
related differences in RCC presentation of all operated tumours
between 1995 and 2005 in the Netherlands, using the PALGA database.
Furthermore we assessed the amount of missing pathological data in our
cohort and related trends in missing diagnoses.
MATERIAL AND METHODS
Patient selection
All excerpts from patients who underwent radical and partial
nephrectomy for a primary renal tumour during the period 1995-2005
were retrospectively retrieved from the prospectively collected PALGA
database. This database automatically collects abstracts from all
pathology reports generated in all pathological laboratories in the
26
27
Chapter 2
Netherlands on a daily basis7. Age at surgery and gender are mandatory
in each report.
The following terms were used to select renal tumours: kidney,
metanephric adenoma, chromophobe adenoma, eosinophilic adenoma,
adenopapilloma, adenoma and all malignancies except carcinoma in
situ. Tumour biopsies, primary renal pelvic tumours, ureteric tumours and
metastases were excluded (as described in our previous study 8).
To attain a cohort of RCC patients, rare kidney tumours were excluded,
see Figure 1.
AGE AND GENDER RELATED DIFFERENCES IN RCC IN A EUROPEAN COHORT
Statistical analyses
To evaluate the influence of age on gender related differences patients
were divided into five cohorts based on their age at surgery (40 years or
younger; 41 through 50; 51 through 60; 61 through 70; and older than 70
years). Separate analyses were done for each sub-cohort. To evaluate
whether our results would be better represented using standardized
age groups, we performed an additional evaluation based on the World
Health Organisation (WHO) age groups (≤44; 45-64; 65-74; 75-84;
≥85 years) 11. Continuous variables between genders were compared
by the independent samples T–test. The Chi-square test was used for
comparison of categorical variables.
Trends were evaluated using the Chi-square Linear-by-Linear association.
All tests were two-tailed and a p-value of 0.05 was considered statistically
significant. Data was assed using Predictive Analytics Software Statistics
18.0.
2
RESULTS
Of the 11619 patients included 7085 (61.0%) were male and 4534 (39.0%)
were female. Table 1 displays detailed patient’s characteristics of the
entire cohort. Gender differences in incidence, age and tumour size
are described in table 2 and differences in tumour stage in table 3. The
most notable discrepancies between genders in the age sub-cohorts are
described below.
Figure 1.Selection algorithm for study cases
Variables
The following variables were analysed: gender, age at surgery, maximal
tumour diameter in centimetres (as mentioned in the pathology report) and
histological subtype. Tumours were staged according to the TNM 2002
classification9 and Fuhrman grade was converted into a 3-tiers grading
system merging grade 1 with grade 210.
28
Sex distribution
The male to female ratio was 2:1 in ages 41-60 years and nearly equally
divided in the oldest patients.
Age at surgery
A higher mean age at surgery was only observed in women older than 70
years. In patients of 40 years and younger, the mean age was lower in
women than in men.
29
Chapter 2
AGE AND GENDER RELATED DIFFERENCES IN RCC IN A EUROPEAN COHORT
<40 years
Male (n=7085, (61.0%))
Female (n=4534, (39.0%))
p- value
62.6 ± 11.5
7.1 ± 3.7
64.7 ± 12.0
6.8 ± 3.6
<0.001*
<0.001*
Mean age±sd (years)
Mean tumoursize±sd (cm)+
Stage
pT1
pT1a
pT1b
pT2
pT3
pT3a
pT3b
missing
2573 (36.3%)
1161 (16.4%)
1412 (19.9%)
1036 (14.6%)
2327 (32.8%)
967 (13.6%)
1295 (18.3%)
1043 (14.7%)
1827 (40.3%)
836 (18.4%)
991 (21.9%)
705 (15.5%)
1249 (27.5%)
485 (10.7%)
727 (16.0%)
692 (15.3%)
<0.001*
0.004*
0.01*
0.17
<0.001*
<0.001*
0.002*
-
2700 (38.1%)
1810 (39.9%)
0.051
152 (2.1%)
94 (2.1%)
0.79
616 (8.7%)
3617 (51.1%)
188 (4.1%)
2442 (53.9%)
<0.001*
0.003*
1895 (26.7%)
1328 (18.7%)
598 (8.4%)
3264 (46.1%)
1259 (27.8%)
720 (15.9%)
345 (7.6%)
2210 (48.7%)
0.23
<0.001*
0.11
-
Subtype
Clearcell
Chromophobe
Papillary
RCCNOS
Grade
1
2
3
missing
Table 1. Characteristics of the overall population, pT3c and pT4 tumours are not reported in this table.
+
n=9123, * p<0.05
<40 yrs
Number (% of total
cohort)
Ratio male: female
41-50 yrs
51-60 yrs
61-70 yrs
403 (3.5%) 1263 (10.9%) 2711 (23.3%) 3667 (31.6%) 3575 (30.7%)
2.2:1
1.9:1
1.6:1
1.2:1
Mean age(±sd) male
(years)
35.2 (5.4)
46.3 (2.7)
55.7 (2.9)
65.8 (2.8)
75.8 (4.0)
Mean age (±sd) female
(years)
33.2 (6.9)
46.1(2.9)
55.8 (2.8)
65.8 (2.8)
76.4 (4.2)
0.001*
0.30
0.37
0.48
<0.001*
Mean tumor size(±sd)
male (cm)
6.7 (4.4)
7.9 (4.2)
7.3 (3.7)
7.0 (3.7)
6.7 (3.4)
Mean tumor size (±sd)
female (cm)
6.9 (4.4)
7.1 (4.1)
6.9 (3.9)
6.8 (3.8)
6.6 (3.1)
0.65
0.77
0.03*
0.43
0.25
p-value
Table 2. Sex ratio, mean age and mean tumour size in men and women in the different age cohorts.
*p<0.05
30
n (%)
pvalue
41-50 years
n (%)
pvalue
51-60 years
n (%)
61-70 years
pvalue
n (%)
pvalue
>70 years
n (%)
pvalue
2
Stage
pT1
pT2
pT3
Male
111 (45.9%)
Female 66 (41.0%)
Male
46 (19.0%)
Female 34 (21.1%)
Male
50 (20.7%)
Female 22 (13.7%)
0.33
0.60
0.07
310 (35.9%)
165 (41.3%)
169 (19.6%)
67 (16.8%)
248 (28.7%)
92 (23.0%)
0.07
0.23
0.03*
614 (34.5%)
378 (40.6%)
300 (16.8%)
176 (18.9%)
596 (33.5%)
221 (23.8%)
0.002*
0.18
<0.001*
841 (37.4%)
571 (40.2%)
277 (12.3%)
201 (14.2%)
768 (34.2%)
413 (29.1%)
0.09
0.11
0.001*
697 (35.7%)
647 (39.9%)
244 (12.5%)
227 (14.0%)
665 (34.1%)
501 (30.9%)
0.01*
0.19
0.04*
Table 3. Tumour stage (TNM 2002) in men and women by age cohort.
*p=<0.05
Pathology
A significantly women smaller tumour size was only seen in patients
between 51 and 60 years (p=0.03). There was a significant increase in
the number of small renal masses (size ≤4cm) from 1995-2005 (21.7% to
27.2%; p<0.001), mainly because an increase in males (21.0% to 28.0%,
p<0.001; females 22.8%-26.0%, p=0.22).
From the age of 51 onwards the incidence of the papillary subtype was at
least twice higher in men than in women (p<0.001).
Grade 2 was less frequent in women aged 61-70 (p=0.02) and older than
70 years compared to men (p<0.001).
>70 yrs
1.5:1
p-value
Age cohorts
Stage
Tumour stage pT3 was less frequent in women, except in patients younger
than 40 years. Compared to their male counterparts, pT1 tumours were
more frequent in women aged 51-60 (p=0.002) and older than 70 years
(p=0.01).
WHO based-age categories
Using the WHO based age groups patient distribution was as followed;
≤44 years, n=764; 45-64 years, n=4903; 65-74 years, n=3885; 75-84
years n=1920; ≥85 years, n=147. Women were younger than men in the
group ≤44 years (p=0.001) and older in the group 45-64 (56.5 vs. 55.9
years, p<0.001) and 75-84 years (78.2 vs. 77.9 years, p=0.01). Women
had significantly smaller tumour size between 45 and 64 years, p=0.001)
and ≥85 (p=0.004). More T1 tumours (resp. p=<0.001, p=0.01) and less
T3 tumours (resp. p<0.001, p=0.008) were seen in women compared to
men in patients 45-64 and 65-74 years.
31
Chapter 2
AGE AND GENDER RELATED DIFFERENCES IN RCC IN A EUROPEAN COHORT
Missing data
Age and gender had no missing values. Tumour size was missing in
21.5%, but stage was determined in 85.1% of the cases. The percentage
of tumours with a missing stage (14.9%) and grade (47.1%) diminished
during the decade for both genders (p<0.001).
Between 1995 and 2005 the frequencies of the Clear Cell, Papillary and
Chromophobe subtype increased and tumours regarded as RCC not
otherwise specified (NOS) (overall 52.2%) decreased in both men and
women (p<0.001, except Papillary subtype in women (p=0.002)).
These observations are shown in Figures 2 and 3.
2
Figure 3. Percentages of RCC subtypes by year
DISCUSSION
Figure 2. Percentages of missing pathological data by year
This study explored the age distribution of gender discrepancies of RCC at
the time of surgery. Our data contained all operated renal tumours during
one decade in the Netherlands. Gender related age differences were only
observed either in patients older than 70 years or younger than 40. Overall
the male to female ratio was 2:1 in patients between 41 and 60 and
decreased to 1.2: 1 in patients older than 70 years.
Women presented with less pT3 tumours from 40 years onwards,
although statistical differences in tumour size were only found in the range
51-60 years. From 50 years onwards Papillary subtype was twice more
prevalent in men than in women. Missing data on subtype and grade was
considerable, but decreased significantly over time.
In concordance with large population based US studies assessing gender
differences in RCC 1,2,12, overall women had a higher age at surgery
32
33
Chapter 2
compared to men. However in our data higher age in women was only
observed in patients older than 70 years. Between ages 41 -70 mean age
at surgery was the same for both genders and in the subgroup younger
than 40 years women were younger. The pronounced age-gender
differences observed in the latter group could not compensate for the
larger group of patients older than 70 years.
Age-gender related differences of RCC at surgery have been scarcely
explored and in general literature regarding RCC in elderly patients is
limited.
An important confounder of our observations can be the overall survival
in the general population. In the Netherlands the male:female ratio for
persons older than 70 years between 1995 and 2005 was approximately
1:1.6 13. This could have led to a higher crude number of women operated
for RCC at an older age compared to their male counterparts. Other
factors that could have modulated the performance of surgery as the
presence of co-morbidity were not recorded in the database.
The overall incidence of RCC reported in males is approximately 1.6
times higher than in females 1,2,12. Thompson et al, including surgically
treated RCCs between 1989 and 2005 (n= 1720) found an equal male:
female ratio between 40 - 59 and 60- 79 years (1.8:1) 14. In a European
multicentre study (n=4774 operated RCCs; 1976 through 2004) the
male: female ratio differed in patients ≤ 40 years (1.2:1) and ≥80 years
(1.5:1) from the classical ratio of 2.1:1 15. A German single centre study
of operated RCCs showed similar findings to the current study. The
frequencies in males and females were almost equal in patients aged 75
and older16.
The conflicting findings presented above could be explained by a better
overall survival in women, but also by the different inclusion periods of
the studies and by differences in local treatment policies regarding elderly
patients. The number of people operated in the eight decade of life is less
compared to younger patients for obvious reasons (co-morbidities, less
life expectancy). A conservative policy was frequently adopted in older
patients before implementation of ablative techniques early 2000 (in the
Netherlands from 2003) 17,18.
In spite of the use of different Staging Systems, women present with lower
stage tumours than men 1,2,6,12,19. Using the 2002 TNM we confirmed the
previous findings 2 of overall higher frequency of pT1 tumours and a lower
34
AGE AND GENDER RELATED DIFFERENCES IN RCC IN A EUROPEAN COHORT
incidence of pT3 tumours in women. Aron et al 1 reported a mean tumour
size of 6.1 and 5.9 cm for males and females respectively. Our data also
showed a consistent smaller tumour size in females, although the number
of small renal masses increased significantly in the study time only in
men. In comparison with the US reports, tumours in the Netherlands
were a mean 1.0 and 0.9 cm larger for males and females respectively
during the study period. As the rate of incidental diagnosis increased in
the time frame of all these studies, one can argue that less abdominal
investigations were performed in Europe, since the mean ages reported
by others were also lower (resp. 2.3 and 0.9 years for females and males)
than our mean ages1.
2
As in the literature 1,2, our series confirms the lower frequency of grade
2 tumours in women compared to men. Although the 3 tiers Fuhrman
grading used in the present study do not allow for a specific distinction
between the lowest grades categories, our study supports the prevalence
of lower grades in females. The Fuhrman grouping in 3 categories
was primed in order to give uniformity, reduce bias and increase the
interobserver concordance20. As others, we found men to have more
papillary tumours, without an adequate population-based explanation1,2,21.
Using WHO age-based groups we observed a larger tumour size
around the fifth decade and older age in women in the seventh decade.
In the largest age group (45-64 years, 42% of the cohort), age-gender
differences were statistically significant for almost all variables. Small
differences might be more pronounced when evaluated in large groups.
In our opinion the age categories in our study provide a more even
distribution of patients among the groups than the WHO age-based
groups and therefore a more sound statistical comparison.
The presence of missing data seems unavoidable in retrospective
epidemiological studies. In our study these percentages did not differ from
previous published studies on the same subject 1,2. Although Aron et al1
presented a cohort with complete data, this was achieved by excluding
approximately 52% of their initially collected data. Missing data on stage
and grade was present in 48% of their original data. Woldrich et al 2
reported an equal amount of missing data on stage (13%), subtype (78%)
and grade (38%) as in the present study. Therefore not only in our study
but also in the precedent ones, a careful interpretation is required when
results concerning grade and subtype are regarded. Like others, we can
35
Chapter 2
only extrapolate data based on the large sample size.
The relevance of missing subtype remains debatable. Firstly tumours
diagnosed as RCC NOS are most likely ClearCell tumours, considering
that the trend in simultaneous decrease in RCC NOS tumours is followed
by the most prominent increase in the Clear Cell subtype. Furthermore
when adjusting for TNM stage, the different histological subtypes have not
been showing significant survival differences 22.
A different matter is the presence of missing grade as Fuhrman grade
has shown prognostic value for predicting survival 23. Despite these
findings, grade and subtype are currently not incorporated in the last TNM
24
. If future refinements in prognostic pathological parameters will lead
to incorporate grade and subtype to the TNM remains unknown albeit
possible.
The age-gender related differences of RCC found in our study might
be of clinical consequence. Although millimetre differences in size will
not determine the choice of the surgical technique, if women from 41
years onward have less pT3 tumours, they would be more eligible for
NSS, contrasting the current tendency of women being treated by RN
instead of PN 25. Conversely the higher incidence of Papillary subtype in
men compared to women from 51 years onwards might also prompt the
preference of NSS technique over RN, when feasible. If confirmed, the
present epidemiological data may play a role in the treatment algorithm of
RCC in both genders.
Further research should focus on evaluating outcomes of different
treatment policies in elderly patients outside institutional frames and based
on wider clinically- based data.
Limitations
The main limitations of this study were the absence of survival data
and clinical antecedents that could have been acting as confounders or
determinants. The anonymous character of the PALGA database did not
permit the retrieval of follow-up data, precluding analysis on survival.
Further limitations are the smaller sample of our cohort and the presence
of missing data. As commented above, this seems inherent to all
retrospective databases and can only be overcome by strict data collection
protocols at national level. This limitation, as well as the smaller sample
size can be balanced by the fact that our database provided a complete
national coverage as opposed to the 26% and 75% nationwide coverage
36
AGE AND GENDER RELATED DIFFERENCES IN RCC IN A EUROPEAN COHORT
of the US databases used for similar studies1,2. Consequently our data
offers a complete picture on trends and gender differences of a decade. A
further lesson can be learned when trends in reporting are assessed.
2
CONCLUSIONS
In an analysis of all operated RCC tumours in the Netherlands an older
age in women presenting at surgery for RCC, was only observed in
patients over 70 years. The male to female ratio differed with age and
was almost equal in patients of 70 years of age and older (1.2:1). Women
presented with less pT3 tumours than men from the age of 41 years
onward and had significant smaller tumour size only between 51-60 years.
Missing data on grade was substantial but diminished significantly
between 1995 and 2005.
AKNOWLEDGEMENTS
We acknowledge the PALGA foundation for providing us with the study
data.
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